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Subjects

Abstract

Objective:

Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.

Subjects:

Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.

Results:

We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10−7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue.

Conclusion:

Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Acknowledgements

KKN was supported by a National Cancer Institute training grant: Cancer Prevention Training in Nutrition, Exercise and Genetics (R25CA094880). LFR was supported by the Cardiovascular Disease Epidemiology Training Grant from the National Heart, Lung and Blood Institute (T32HL007055) and the American Heart Association (AHA) predoctoral grant (13PRE16100015). The Population Architecture Using Genomics and Epidemiology (PAGE-I) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The Population Architecture Using Genomics and Epidemiology (PAGE-II) program is funded by the National Human Genome Research Institute (NHGRI), with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI) and U01HG007419 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at PAGE website (http://www.pagestudy.org). The data and materials included in this report result from a collaboration between the following studies: The ‘Epidemiologic Architecture for Genes Linked to Environment (EAGLE)’ is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). The data set(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. The Vanderbilt University Center for Human Genetics Research, Computational Genomics Core provided computational and/or analytical support for this work. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through NHGRI (HG004802, and HG007397) and the NHGRI PAGE program (U01HG007397, U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (CA164973, R37CA54281, R01 CA 063464, P01CA33619, U01CA136792 and U01CA98758). The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000220. Funding support for the ‘Epidemiology of putative genetic variants: The Women’s Health Initiative’ study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). Funding support for the ‘Exonic variants and their relation to complex traits in minorities of the WHI’ study is provided through the NHGRI PAGE program (U01HG007376, U01HG004790). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32 and 44221. WHI PAGE-II is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HSN268201100003C, HHSN268201100004C and HHSN271201100004C. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000227. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01HG007416, U01HG004803 and its NHGRI ARRA supplement). The following CALiCo studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Coronary Artery Risk Development in Young Adults (CARDIA) study is supported by the following National Institutes of Health, National Heart, Lung and Blood Institute contracts: N01-HC-95095; N01-HC-48047; N01-HC-48048; N01-HC-48049; N01-HC-48050; N01-HC-45134; N01-HC-05187; and N01-HC-45205. CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C) and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. The Hispanic Community Health Study/Study of Latinos (SOL) was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). Additional support was provided by 1R01DK101855-01 and 13GRNT16490017. The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. The Cardiovascular Health Study (CHS) is supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants HL080295 and HL087652 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. CHS GWAS DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition, the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521 and R01 HL109301. The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000223 (ARIC), phs000236, (CARDIA), phs000301 (CHS), phs000555 (HCHS/SOL). The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service. GenNet is one of four networks in the Family Blood Pressure Program, established in 1995 and supported by a series of agreements with the NIH National Heart, Lung and Blood Institute. Samples and data from The Charles Bronfman Institute for Personalized Medicine (IPM) BioMe Biobank used in this study were provided by The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai (New York). Phenotype data collection was supported by The Andrea and Charles Bronfman Philanthropies. Funding support for the Population Architecture Using Genomics and Epidemiology (PAGE) IPM BioMe Biobank study was provided through the National Human Genome Research Institute (U01HG007417). The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000925. The Hypertension Genetic Epidemiology Network (HyperGEN) study was supported by National Heart, Lung and Blood Institute contracts HL086694 and HL055673. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG007419, U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. We gratefully acknowledge Dr Ben Voight for sharing the Metabochip SNP LD and minor allele frequency statistics estimated in the Malmö Diet and Cancer Study. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions.